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Abstract
Idiopathic intracranial hypertension (IIH) is a condition of significant morbidity and rising prevalence. It typically affects young people living with obesity, mostly women of reproductive age, and can present with headaches, visual abnormalities, tinnitus and cognitive dysfunction. Raised intracranial pressure without a secondary identified cause remains a key diagnostic feature of this condition, however, the underlying pathophysiological mechanisms that drive this increase are poorly understood. Previous theories have focused on cerebrospinal fluid (CSF) hypersecretion or impaired reabsorption, however, the recent characterisation of the glymphatic system in many other neurological conditions necessitates a re-evaluation of these hypotheses. Further, the impact of metabolic dysfunction and hormonal dysregulation in this population group must also be considered. Given the emerging evidence, it is likely that IIH is triggered by the interaction of multiple aetiological factors that ultimately results in the disruption of CSF dynamics. This review aims to provide a comprehensive update on the current theories regarding the pathogenesis of IIH.
- NEUROOPHTHALMOLOGY
- HEADACHE
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Introduction
Idiopathic intracranial hypertension (IIH) is a disease characterised by the presence of elevated intracranial pressure (ICP) in the absence of a clear underlying aetiology.1 2 Variously referred to as pseudotumour cerebri or benign intracranial hypertension, IIH represents a condition of rising prevalence and morbidity, affecting overweight females of reproductive age at a number fourfold higher than that of men.3–5 Incidence varies owing largely to geographically heterogeneous data, however, population estimates portray rates of IIH to exist between 0.03 and 7.8 per 100 000.6 7 The highest incidence is observed in women living with obesity and a history of recent weight gain, though social deprivation, race and geographical location are also considered contributory risk factors.8 Concerningly, incidence has more than doubled over the past two decades, closely associated with rising rates of obesity. Through the largest analysis to date of patients with IIH across England, investigators found a 108% rise in the incidence of disease from 2.6 per 100 000 in 2002 to 4.69 per 100 000 in 2016, increasing to 7.69 per 100 000 when stratified for females of reproductive age.3 Similar findings were observed in cohorts studied in the USA, Wales, Sweden and the Middle East.6–9 Given the strong association between body mass index (BMI) and IIH, further rises in prevalence are expected as the burden of obesity continues to climb worldwide.10 IIH additionally represents a substantial economic concern as resultant morbidity manifests as lost income and increased healthcare utilisation costs, increasing fivefold in the past decade.3 11
Though a small proportion of individuals may be asymptomatic, headache is well recognised as the most common symptom in IIH.12 Considered a secondary headache disorder, the phenotype is highly variable and can resemble those of primary headache disorders with migraine-like characteristics common.13 Other typical symptoms in patients with IIH include pulsatile tinnitus and visual abnormalities, including transient visual obscurations, diplopia or in severe cases, visual loss.14 Further morbidity arises through cognitive impairment, increasingly recognised to result in a loss of quality of life.15 Diagnosis typically requires the presence of papilloedema and direct evidence of raised ICP as demonstrated by elevated lumbar puncture opening pressure or rarely, by invasive ICP monitoring.2 Although neuroimaging may identify radiological features supportive of IIH, utility surrounds the exclusion of alternative causes of raised ICP. Once confirmed, treatment approaches focus on ICP reduction and symptom relief. The first consensus guideline in 2018 outlines key management strategies, including weight loss, pharmacological therapy with carbonic anhydrase inhibitors and indications for surgical management.16
Despite established diagnostic criteria and management principles, there is still a fundamental gap in understanding the pathogenesis of IIH, compromising the development of more targeted therapy. The aetiology is presumed to involve a disruption of cerebrospinal fluid (CSF) homeostasis, resulting in elevated ICP. Previous studies have investigated whether IIH occurs through increased CSF production via the choroid plexus, impaired absorption through arachnoid granulations in the cortical venous sinuses, or due to venous hypertension secondary to stenotic structural abnormalities. To date, no single explanation has been found.1 16 Yet, the marked gender and weight disparity associated with IIH is indicative of a possible metabolic or hormonal aetiology, raising questions about the idiopathic nature of this condition.
An emerging hypothesis relates to the role of the glymphatic system, a recently identified series of perivascular spaces surrounding cerebral arteries and veins. Presumed in effect similar to the peripheral lymphatic system, these spaces represent a direct connection between the cerebrovascular system and the CSF, allowing para-arterial exchange of solutes between compartments prior to paravenous efflux of waste and excess interstitial fluid.17 Impaired glymphatic drainage has been implicated in the development of other neurological conditions including normal pressure hydrocephalus, with increasing evidence towards a role in the pathogenesis of IIH.18 19
Pathophysiology
Numerous theories proposing to account for the rise in ICP focus on an overall increase in CSF volume (figure 1). One main hypothesis attributes the rise in volume directly to an increase in overall CSF production due to dysfunctional epithelial cells and water-permeable channels within the choroid plexus. Another suggests volumetric change and subsequent pressure rise occur due to decreased CSF absorption through arachnoid granulations within venous sinuses.1 20 Changes in venous pressure and outflow mediated by mechanical stenoses have also been implicated in the pathogenesis of IIH, observed through the potentially therapeutic effect of cerebral venous sinus stenting.21 The role of the newly identified glymphatic system requires further exploration and inclusion in any mechanistic modelling of raised ICP in IIH, with dysfunction at this level associated with changes in lymphatic CSF outflow.22 Although any underlying pathophysiological mechanism should be able to account for the striking phenotypic correlation with the female sex and weight gain in patients with IIH, a single unifying link remains unclear.
Proposed pathophysiological mechanisms for the elevation in intracranial pressure seen in patients with IIH. Alterations in CSF production have been demonstrated with upregulation of the Na+/K+ATPase transporter activity or dysfunction of AQP1 channel function, both located on the apical surface of the choroid plexus epithelial cells. While carbonic anhydrase inhibitors are thought to reduce CSF production via inhibition of the Na+/K+ATPase transporter and downregulation of AQP1 expression, androgen excess, glucocorticoid dysfunction and increases in circulating adipokines are proposed to directly impact CSF secretion rate through upregulation of these water transport mechanisms. Reduction in CSF reabsorption or drainage is thought to occur by numerous factors. Alterations in venous outflow, perineural CSF drainage rates and glymphatic function are proposed to contribute to a reduction in the clearance of CSF and an increase in congestion of the extraventricular subarachnoid spaces, driving the rise in intracranial pressure observed in these patients. Despite recognised risk factors and increasing evidence for multiple mechanisms, a single unifying theory or pathological causative event remains unknown. 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; AQP1, aquaporin 1; AQP4, aquaporrin 4; CSF, cerebrospinal fluid; IIH, idiopathic intracranial hypertension.
CSF production and hypersecretion
CSF originates and spreads through the ventricular and subarachnoid spaces of the brain and spinal cord. CSF surrounds individual cells and is vital in the distribution of nutrients, hormones and metabolites, the removal of waste products, and in direct protection of the brain against mechanical forces. The total static CSF volume in adults is estimated to be 125–150 mL, renewed 3–4 times over a 24-hour period. The choroid plexus is the primary site of CSF production, producing 80% of CSF. Rich in vascular supply, it contains highly organised networks of ependymal cells, and is found in all four ventricles of the brain, surrounding terminal fenestrated capillaries to generate the blood–CSF barrier.23 Abundant in transporters at both the basal and apical surfaces, the epithelial structure of the choroid plexus regulates the composition of CSF by selectively controlling the movement of solutes and water.24 Sodium ions are quantitatively the most important solute in CSF secretion, with direct inhibition of the Na+/K+ATPase transporter on the apical surface reducing CSF secretion by up to 80%.25 Transcellular movement of these ions and the subsequent osmotic gradients generated allows for the transport of water into the ventricles, mediated by aquaporin-1 (AQP1) channels, on the apical cell surface.26 27
Many attempts have been made to link CSF hypersecretion to the pathogenesis of IIH. Though early CSF hydrodynamic studies suggested higher net rates of CSF production in young women living with obesity, these outcomes have not been replicated.28 29 Phase contrast MRI attempting to provide evidence of hypersecretion through indirect measurements of CSF flow have shown changes in mean flow rate without hypersecretion, whereas CSF infusion tests demonstrate increased CSF pressure through reduced craniospinal compliance, not overproduction.30 31 A recent novel study using an automated peristaltic pump device demonstrated an increased net CSF production rate in patients with IIH compared with controls, though the accuracy of this measurement is unclear.32 Animal models used to investigate CSF modulation by diet showed an increase in CSF secretion rate when subjects are exposed to a high-fat diet, hypothesised to be due to cortisol-induced increased intracellular Na+transport. Though a similar process is thought to occur in humans, no evidence has been found to date.33 Furthermore, human neuroimaging studies have not shown any morphological changes at the choroid plexus in IIH.
Given their contribution to CSF production, the role of AQP channels in the development of IIH has been suggested. AQP4 is the most abundant water channel in the central nervous system (CNS), located at key interfaces between the brain parenchyma and water-containing compartments. Although anti-AQP4 antibodies produce a spectrum of neurological diseases with CNS demyelination, no association between anti-AQP4 antibodies and IIH has been found.34–36 Conversely, evidence for a pathogenic role of the AQP1 channel in IIH pathogenesis is stronger. AQP1 is directly involved in the production of CSF, expressed on the ventricular-facing apical membrane of the choroid plexus. AQP1 null mice models demonstrate a 25% reduction in CSF production from the choroid plexus, whereas an increase in CSF production is observed in choroid plexus tumours with increased AQP1.37 38 Alterations in AQP1 function have also been shown to correlate to changes in ICP, with upregulation of this protein seen in obesity, exposure to retinoids and glucocorticoid use, known risk factors for the development of IIH.39 Acetazolamide, a carbonic anhydrase inhibitor commonly used in the treatment of IIH, has also been shown to downregulate the expression of AQP1 and reduce CSF production in animal models.40 These factors suggest a pathogenic role of AQP1 in the formation of raised ICP through channel-mediated hypersecretion of CSF, however, evidence for causality in IIH remains scarce.
Altered CSF reabsorption
The understanding of CSF movement has changed over time, and several potential levels of obstruction have been hypothesised to cause IIH through impaired reabsorption.
Arachnoid granulations
The most well-recognised pathway for CSF reabsorption occurs through arachnoid granulations, anatomical projections of arachnoid mater, located within dural venous sinuses. Representing a direct barrier between the subarachnoid space and venous circulation, CSF is reabsorbed through hydrostatic gradients driven by higher pressure within the subarachnoid space. However, the efficacy of this process has been questioned, with the importance of these structures based on older anatomic studies.41 42 More recently, marked heterogeneity in arachnoid granulation size, frequency and distribution has been demonstrated, with normalisation of ICP despite a physical absence of arachnoid granulations.43 The importance of arachnoid granulations in CSF physiology likely has been overstated and presumably plays a greater role in pressure regulation than true reabsorption.
Venous system abnormalities
Anatomical abnormalities of the venous sinus system are common in patients with IIH and typically occur within the transverse sinuses. Intrinsic stenoses of discrete anatomical abnormalities may alter venous flow dynamics within the lumen of the vessel.44 Though it has been suggested that this could arise in IIH from microthrombi secondary to a hypercoagulable state, direct evidence is lacking and stenoses typically result from enlarged arachnoid granulations.45 46 Alternatively, long-segment sinus stenoses may also exist without an endoluminal abnormality secondary to increased ICP, leading to venous compression and a perpetuating cycle of dysfunction.41 47 Regardless of the mechanism, stenotic vessels result in reduced venous outflow and a rise in central venous pressure, altering the pressure gradient between the CSF and the venous circulation and leading to a presumed excess of CSF within the subarachnoid and perivascular spaces.1 20 A close correlation has been shown between intracranial venous sinus pressure level and CSF opening pressure, with a proportional rise in ICP demonstrated.48 Consequently, the radiological presence of venous sinus stenosis in patients with IIH is frequently used as an indicator of the likelihood of the outflow resistance hypothesis. However, it still remains unclear whether venous stenosis represents the cause or the consequence of raised ICP, especially given the proven reversibility of extrinsic stenoses by therapeutic reductions in ICP.49 50 Importantly, there is no strong association between the degree of anatomically defined stenosis and the clinical symptoms, severity or outcomes of disease.51 52
Lymphatic outflow pathways
The lymphatic outflow pathway presents an alternative mechanism for reabsorption and counters a historical belief that the CNS lacked a functioning lymphatic drainage system.22 CSF drainage into the extracranial lymphatic system occurs by two key mechanisms: perineural routes of drainage into the cervical lymphatic system within the sheath of several cranial nerves exiting the orbit of skull base, and through the subarachnoid space along spinal nerves into lymphatic vessels within the epidural tissue.53 54 Animal model-based in vivo imaging of fluorescently labelled albumin demonstrated a greater elimination rate of CSF across the cribriform region within the sheath of the olfactory nerve into the cervical lymphatic system when compared with other routes, suggesting this to be a dominant pathway.55 Cumulatively, these conduits have been suggested to represent the major route of drainage of CSF from the subarachnoid space, greater than that of the venous outflow; however, human-based studies are yet to confirm this finding.
Glymphatic system
A recently identified CNS-based fluid transport pathway, the ‘glymphatic system,’ connects the two existing pathways and provides another route for CSF drainage. Named for a dependence on glial water flux and a pseudolymphatic function, the glymphatic system establishes a role for CSF clearance as a means to remove waste products and extracellular solutes from the CNS.17 This drainage pathway consists of perivascular spaces surrounding cerebral arteries and veins and proposes a continuous interchange of CSF and interstitial fluid within the brain parenchyma, driven largely by the influx of CSF through the subarachnoid space.41 Exchange occurs across a glial barrier, demarcated by the presence of astrocytic endfeet surrounding cerebral vasculature and mediated by a high density of AQP4 channels. The importance of this was demonstrated with AQP4-null mice models depicting a marked reduction in the clearance of toxic metabolites and solutes across this path.17 56 The subsequent efflux of solutes from glymphatic exchange is presumed to enter the perivenous space before reabsorption occurs via vascular arachnoid granulations within the venous sinuses, direct flow into the lymphatic outflow system or by transependymal reabsorption back into the ventricles.42 Given its postulated role in waste and metabolite clearance, pathological dysfunction of the glymphatic system has been suggested to play a role in the development of numerous neurological diseases.57
Glymphatic and lymphatic CSF outflow pathway dysfunction has been suggested as a mechanism for the pathogenesis of IIH, likely coexisting in tandem with a restriction in venous outflow, though debate remains regarding the initial causative event.22 Evidence of possible glymphatic dysfunction has been shown within a small homogenous population comprising patients with IIH and overweight controls. Using volumetric MRI sequences, overall increases in extraventricular CSF and interstitial volumes were seen within the subarachnoid and perivascular spaces of those with IIH, implying an impairment of CSF homeostasis.58 A comparable study using a gadobutrol CSF-tracer demonstrated similar findings, with decreased clearance within perivascular and interstitial spaces, most notably within the frontal and temporal regions.59 Changes in ICP have also been implicated in the dilatation of ocular perivascular glymphatic channels in patients with IIH.60 Furthermore, common radiographic findings in IIH are also thought to suggest glymphatic dysfunction, observed as lymphatic and perineural CSF outflow abnormalities. Congestion of the extraventricular subarachnoid space and dysfunction of the glymphatic system is presumed to lead to overflow of the lymphatic outflow path, characterised as an excess of CSF seen radiologically around numerous cranial nerves. This most commonly includes the optic nerve depicted by optic nerve sheath dilatation and tortuosity, but can also include Meckel’s cave dilatation, a surrogate of CSF within the trigeminal nerve sheath, and enlargement of Dorello’s canal representing involvement of the abducens nerve.
Although no study has reliably demonstrated evidence for a pathological mechanism behind this glymphatic failure, it has been suggested that this might occur through alterations at the glia-neuro-vascular interface, specifically the astrocytic endfeet processes containing AQP4 channels.59 61 Given the strong female predilection and association with obesity, both autoimmune and inflammatory causes for this dysfunction have been speculated, though no cause identified.
Obesity and neuroendocrine dysfunction
The prevalence of IIH is substantially higher in patients who are overweight or have obesity, and the risk of disease disproportionately rises in relation to increasing BMI.62 Small amounts of weight gain are associated with disease development in cohorts with and without obesity, particularly when occurring within the preceding 12 months.63 Disease severity also increases in proportion to weight, with poorer prognoses and higher disease recurrence rates seen in patients with BMI>40 kg/m2.64 65 The benefit of weight loss provides further evidence towards pathogenesis, with a reduction in weight associated with significantly lowered levels of ICP, reductions in papilloedema, improved visual function and headache reduction.66 Although obesity is clearly associated with IIH, the mechanism remains unknown and presumes a multifactorial origin, given the prevalence of patients living with obesity but without IIH.
Obesity has been hypothesised to result in increased intra-abdominal pressure, resulting in elevated central venous pressure and upstream impairment of cranial venous outflow.67 The distribution of adipose tissue has also been implicated in causality for IIH. However, these historical theories have been recently challenged. A previous single-centre study of waist-to-hip ratios demonstrated a preference for lower body fat distribution when compared with central adiposity in controls living with obesity.68 However, this notion was refuted using dual-energy X-ray absorptiometry scanning as patients with IIH portrayed typical centripetal fat distribution, similar to BMI and gender-matched controls. Truncal fat mas also significantly correlated with LP opening pressure, not BMI.69 70 The relationship between obesity and IIH development in men is less clear, as males typically exhibit lower levels of obesity than females. Conversely, males experience greater vision loss and higher rates of obstructive sleep apnoea.71
Obesity is considered a chronic inflammatory condition associated with a number of proinflammatory cytokines, chemokines, adipokines and hormones.72 Numerous studies have sought to identify a characteristic inflammatory profile of IIH. However, no study has provided a clear correlation between a cytokine or adipokine level and BMI, IIH clinical syndrome or disease duration to date. One study identified elevated levels of CCL2 within the CSF of IIH patients when adjusted for BMI.73 However, a larger cohort failed to demonstrate a difference between IIH, controls living with obesity and a number of inflammatory proteins.72 Elevated rates of serum interleukins (IL), specifically IL-1β, IL-2, IL-4, IL-10, IL-12 and IL-17 have been shown, with conflicting results regarding TNF-α.74–77 Results of these studies should be interpreted with caution though and are limited by small sample sizes, heterogeneous populations, inconsistent control groups and variabilities in cytokine detection and measurement.
Leptin, an adipokine secreted by adipose tissue, has been of particular interest. Used primarily in the regulation of energy homoeostasis, studies have provided conflicting results reporting elevations in both CSF and serum leptin in individuals with IIH. It was postulated that chronic CSF leptin elevation may induce CSF hypersecretion through increased Na+/K+ATPase activity at the choroid plexus, given a similar mechanism in the kidney. However, these studies were limited by sample size, control selection and fasting status, therefore, failing to provide a substantial link between leptin level and CSF dysregulation.78 79 More recently, in a larger prospective cohort study of 97 IIH patients, fasted serum leptin levels were elevated in those with IIH when compared with age, sex and BMI-matched controls, demonstrating serum hyperleptinaemia in excess of that observed in obesity. However, no differences in CSF and serum/CSF ratio or serum leptin levels and LP opening pressure were seen.70 This finding suggests that hyperleptinaemia is unlikely to drive disordered CSF dynamics and instead is more a reflection of systemic metabolic dysregulation and increased obesity risk in patients with IIH.
Furthermore, patients with IIH exhibit an increased risk of type 2 diabetes mellitus and cardiovascular morbidity, suggestive of systemic metabolic dysfunction like that seen in polycystic ovarian syndrome.62 80 Patients with IIH and obesity demonstrate an insulin-resistant phenotype of elevated fasting insulin levels and higher markers of insulin resistance when compared with controls.70 Though no elevation in fasting glucose was shown, these patients carry an increased risk of progression to pre-diabetes and type 2 diabetes mellitus in later life. Patients with IIH also exhibit a preference toward truncal obesity, an area most associated with metabolic syndrome and insulin resistance, and it is possible that this vulnerable population group are predisposed to lipogenesis and truncal adiposity through an altered adipose tissue metabolic and transcriptional profile.70 Further evidence of global metabolic dysfunction in IIH has been characterised through use of proton nuclear magnetic spectroscopy, demonstrating dysfunction of the serum and CSF lactate: pyruvate ratio and alterations in ketone body metabolism.81 The former is associated with elevated ICP in hydrocephalus and traumatic brain injury, whereas the latter suggests an upregulation of ketogenesis akin to that in insulin resistance. Metabolic changes in serum and CSF ratio of urea were also correlated with severity of headache in patients with IIH. These findings overall support the hypothesis that IIH occurs on a spectrum of metabolic dysfunction with obesity, insulin resistance and hyperleptinaemia, though it remains unclear how this systemic metabolic dysfunction precisely correlates with altered CSF dynamics (figure 2).
IIH and obesity, postulated mechanisms for the increase in intracranial pressure typical for IIH. Risk of disease rises in relation to increasing weight, with patients demonstrating an increase in centripetal fat distribution which correlates closely with opening pressure. Elevated levels of proinflammatory cytokines associated with obesity are hypothesised to cause fibrosis or inflammation of the arachnoid villi, impairing CSF drainage leading to increases in pressure, while autoimmune causes also remain of suspicion. The distinct pattern of androgen excess and 11B-HSD1 dysregulation seen in IIH provide proadipogenic action further increasing central adiposity, while both are hypothesised to induce CSF hypersecretion through interaction with the apically located Na+/K+ATPase. Though leptin was hypothesised to induce CSF hypersecretion through interaction with the choroid plexus, no direct link has been found and hyperleptinaemia likely reflects systemic metabolic dysfunction. 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; CSF, cerebrospinal fluid; IIH, idiopathic intracranial hypertension.
Hormonal dysregulation
Elevated levels of circulating androgens have been confirmed in IIH, with an androgen excess signature distinct from the typical pattern seen in other metabolic syndromes.82 Significantly higher levels of serum testosterone, and CSF testosterone and androstenedione occur in women with IIH compared with metabolically matched controls.83 Higher serum levels of testosterone and androstenedione were also associated with an earlier age of onset of disease, independent from BMI, though a control cohort was not evaluated.84 Initiation of testosterone therapy in individuals undergoing masculinising gender-affirming hormone treatment can also promote disease onset, reflecting the possible pathogenicity of this androgen within a susceptible population.85 Alternatively, men with androgen deficiency may be at increased risk of IIH, a counterintuitive thought process when linking androgen excess with IIH.86 87 This reflects the sexually dimorphic effects of androgens on human metabolism, suggesting that a level exists of serum testosterone that confers a risk of IIH to women through androgen excess, but a risk to men through relative androgen deficiency.83 88 Though the mechanism for CSF dysfunction with hyperandrogenism is unknown, androgen excess may result in CSF hypersecretion through direct effect on the choroid plexus Na+/K+ATPase.83 IIH may also occur due to the proadipogenic action of androgens and the physiological consequences of abdominal mass accumulation.89 Weight loss has been associated with significant reductions in both testosterone and 5ɑ-reductase activity, correlating with a reduction in disease activity.90 While androgens have been of interest, few studies have assessed the role of oestrogen and progesterone in IIH, with those performed lacking sufficient sample size or matched controls.88
Glucocorticoid dysfunction
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme used to regulate cortisol production within tissue, converting cortisone to active cortisol and amplifying local glucocorticoid concentrations.78 11β-HSD1 is dysregulated in obesity, presumably through a combination of chronic inflammation and macrophage infiltration into the surrounding adipocytes. This results in increased 11β-HSD1 activity within the subcutaneous adipose tissue, elevated cortisol release, increased adipocyte differentiation and higher rates of hepatic gluconeogenesis.91 Systemic 11β-HSD1 dysregulation has also been seen in IIH at rates greater than in obesity alone.92 While this may lead to increased central adiposity, 11β-HSD1 may have a more direct role in the regulation of ICP through altered CSF secretion.88
11β-HSD1 and key elements of the glucocorticoid signalling pathway are expressed and active within the choroid plexus and arachnoid granulation tissue, amplifying intracranial cortisol availability at these sites.93 Increased cortisol at the epithelial choroid plexus is hypothesised to bind to the intracellular glucocorticoid or mineralocorticoid receptors and upregulate the activity of the apically located Na+/K+ATPase, a key transporter in the production of CSF.78 Indirect evidence for this pathway within the IIH population has been demonstrated by correlations between 11β-HSD1 activity and alterations in ICP. A reduction in 11β-HSD1 activity following the introduction of a low-calorie diet correlated closely with a reduction in ICP, identifying weight loss as a potential mechanism for 11β-HSD1 modulation within this population.66 Similarly, surgically mediated weight loss reduced systemic 11β-HSD1 activity within an IIH cohort at rates greater than observed in non-IIH controls undergoing comparable bariatric surgery.92 These findings support the correlation between adiposity and 11β-HSD1 activity and the hypothesis that individuals with IIH carry a separate adipose phenotype different to that in typical obesity. A recent phase II double-blinded randomised placebo-controlled trial to evaluate the effect of a direct 11β-HSD1 inhibitor (AZD4017) in patients with IIH demonstrated an average reduction in ICP of 4.3cmH2O. No significant change in clinical visual parameters, weight or overall BMI were observed.94 However, improvements in lipid profiles, hepatic function and lean muscle mass were shown, suggesting a mild benefit of 11β-HSD1 inhibition to address risk factors associated with the IIH metabolic syndrome.95 Inhibition of 11β-HSD1 activity also improves short-term memory in rodents, suggesting a relationship between glucocorticoid excess and cognitive function and a possible explanation for the deficits experienced by those with IIH.96
Incretins and GLP-1
Evidence is emerging for the role of gut peptides in the modulation of ICP. Glucagon-Like-Peptide-1 (GLP-1) is a hormone secreted from the small intestine that augments pancreatic insulin secretion while promoting satiety and weight-loss.97 GLP-1 induces natriuresis within the kidney by inhibiting the Na+/H+exchanger within the renal proximal tubule.98 Localisation of GLP-1 receptors in the choroid plexus was shown in rodents, suggesting a role in CSF modulation via a similar influence on sodium transport. In patients with IIH, administration of exendin-4, a GLP-1 receptor agonist, confirmed this theory, demonstrating a rapid but also sustained reduction in ICP over the course of treatment, presumably through inhibition of the Na+/K+ATPase transporter activity.99 Though no pathophysiological link has been found between dysregulated GLP-1 function and the development of IIH, translation of the therapeutic benefit of this hormone has been shown in a human population. Some bariatric surgical procedures have been shown to enhance circulating GLP-1 levels, raising the possibility that the therapeutic benefit of these procedures may extend further than weight loss alone in the management of IIH.100 A recent double-blinded randomised placebo-controlled trial with the GLP-1 receptor agonist exenatide produced favourable results, exhibiting a rapid and sustained reduction in ICP, aligning with an improvement in clinical symptoms. In the absence of significant weight loss, these findings further highlight the role of GLP-1 receptors in ICP modulation through a direct impact on CSF secretion.101
Pregnancy
Pregnancy has often been considered a risk factor in the development of IIH, associated with a range of physiological changes postulated to increase ICP. Weight gain, increases in intra-abdominal pressure, thrombophilia and hyperfibrinolysis secondary to a hyperoestrogenic state have all been proposed to promote IIH through alterations in central venous pressure and thrombotic obstruction of CSF reabsorption. However, IIH occurs in pregnant women at approximately the same rate as the general population, and subsequent pregnancies do not increase the risk of disease presentation or recurrence. When occurring during pregnancy, IIH has been shown to present in any trimester, though it is more frequently identified within the first half of gestation.102 Given the paucity of evidence identifying a causal link, it is likely that IIH occurring during pregnancy arises through the same physiological mechanisms as the non-pregnant cohort and previous association occurs due to the overlapping demographic.
Associated disorders and secondary conditions
A number of comorbid or associated conditions have been implicated in the development of raised ICP, often mimicking the presentation of IIH.2 Though a distinction must be made between primary causes of the ‘pseudotumour cerebri syndrome’ (IIH) and secondary causes, the division between the two may remain unclear, with many stratified as risk factors for IIH in the absence of a clear secondary mechanism.4 Endocrinological disorders have been associated with IIH largely through case reports, presumed to occur due to a relative glucocorticoid deficiency hypothesised to reduce CSF absorption and increase resistance to CSF flow.103 Anaemia has commonly been recognised as a risk factor for IIH, although a mechanistic link for the disease is lacking. A recent systematic review suggested anaemia was 44% more common in those with IIH than age-matched and sex-matched controls, with a pooled prevalence of 18.2% among patients with IIH.104 However, IIH patients with anaemia demonstrate shorter disease course and more rapid resolution with correction of anaemia.105 Numerous medications are strongly associated with raised ICP. Vitamin A and its derivatives impart the highest risk for the development of drug-induced intracranial hypertension, with changes in ICP hypothesised to occur through vitamin A-induced augmentation of 11B-HSD1 activity. Retinoic acid derivatives are similarly implicated through increased CSF production and impaired CSF absorption and though tetracycline antibiotics confer the second highest risk, the causal link is unclear.106
Clinical implications and future directions
Refining the understanding of the pathophysiological mechanisms of disease in IIH is of paramount importance to improve clinical outcomes and develop safe and targeted therapeutic interventions. Pharmacological therapy to date has been limited to carbonic anhydrase inhibitors, hypothesised to reduce the rate of CSF production via inhibition of the Na+/K+ATPase transporter. However, recognition of AQP1 channels in the generation of CSF and the effect of acetazolamide on AQP1 expression has suggested a dual benefit not previously well recognised. Topiramate has also proven an attractive therapy in patients with IIH through a direct effect on CSF production and weight loss by appetite reduction.16 Recent advancements in our knowledge of CSF dynamics have brought to light an intriguing role of GLP-1 receptors in the regulation of ICP and highlighted this class of medication as a novel strategy in the treatment of IIH. However, further research into the specific mechanisms by which GLP-1 agonists impact IIH pathophysiology is necessary. Though the recently demonstrated benefit of exendin in a typical IIH population has led to the initiation of a larger, prospective randomised control trial within this cohort in an attempt to increase their application.101
Increasing recognition of venous stenoses in the pathogenesis of IIH has highlighted venous sinus stenting as an appealing therapeutic target. This minimally invasive procedure presents a novel method to restore normal venous drainage and alleviate the signs and symptoms of raised ICP.107 Stent insertion in patients with IIH has been shown to produce a rapid and sustained reduction in ICP over time, however, patient selection is of importance and recommendations are not well established.108 109 The clinical translation of these findings are not immediate and further clarification is required to determine causation compared with association for this factor. Future studies in larger population groups are required to determine the optimum cohort, to increase the utility of this procedure, and to maximise clinical benefit, with one randomised clinical trial currently seeking to answer these questions.110
However, the role of the glymphatic system should not be understated and further investigations into its mechanistic link are vital. The current literature is limited with glymphatic dysfunction in patients with IIH largely theorised, suggested from underpowered studies in homogeneous populations or indirectly from radiological findings. Though an autoimmune or inflammatory based AQP-mediated channelopathy has also been suggested, evidence is lacking, limiting the conclusions that can be made for this population. Identifying the specific cause of dysfunction at the level of the glial-neuro-vascular interface through the pathogenic accumulation of a waste product or the discovery of a channel-specific autoantibody could revolutionise our understanding of this disease and provide novel therapeutic, imaging or biomarker-based diagnostic targets. These findings could allow for earlier recognition, improved disease stratification and more optimised patient outcomes in an attempt to reduce the impact of this disease on the population.
Conclusion
IIH remains a challenging medical and health-economic diagnosis. Despite recent advances, the fundamental understanding of the underlying pathophysiology remains unclear. Raised ICP is the critical component of this disease and continues as the target of current therapeutic options, yet the mechanistic driver of this process has still not been identified, nor has the link to such a specific population group. Disruption to CSF reabsorption poses an attractive hypothesis with increasing recognition and understanding of the role of the veno-glymphatic system in CSF physiology; however, the impact of the neuroendocrine system, the presence of hormonal dysregulation and the role of inflammatory adipokines cannot be ignored. Given the emerging evidence for each, it stands that IIH likely exists through multi-factorial influences, ultimately resulting in disruption of CSF absorption due to veno-glymphatic dysfunction and subsequent overflow of CSF within the subarachnoid and perivascular spaces. Though the last decade has produced a greatly increased understanding of the numerous factors potentially contributing to disease development, further studies are necessary to identify additional therapeutic targets and to explain the inherent vulnerability of this patient cohort.
Methods
MEDLINE via PubMed was searched from inception to 31 May 2022, for articles published in English using the search terms “idiopathic intracranial hypertension”, “pseudotumor cerebri”, “benign intracranial hypertension”, “IIH”, “pathophysiology”, “glymphatic system” and “perivascular space”. Results were then imported and processed via EndNote V.20. Reference lists of key articles identified and published within the past 10 years were screened to identify additional important publications prior to completion of the review.
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References
Footnotes
Contributors BDC: conceptualisation, methodology, writing original draft, reviewing and editing, figure conceptualisation and design. MNLN, SR, PS and OW: reviewing and editing. FB, EJH and JF: reviewing, editing and supervision. AvdW: conceptualisation, writing, reviewing, editing and supervision. All authors contributed to the article and approved the submitted version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests PS has co-authored manuscripts with medical writing provided by Novo Nordisk and Eli Lilly. She is supported by an Investigator Grant from the National Health and Medical Research Council (1178482). JF receives funding from Genzyme and Biogen and has received honorarium from Novartis. AvdW has received travel support and served on advisory boards for Novartis, Biogen, Merck Serono, Roche and Teva. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia.
Provenance and peer review Not commissioned; externally peer reviewed.